In 2010, the World Health Organization (“WHO”) reported that 10% of the adult population in the United States suffered from alcohol use disorders (“AUD”). AUDs have a debilitating effect and are known to lead to 60 medical conditions affecting the immune system, central nervous system (CNS), liver, etc. (Alcohol Research & Health, 2011, 34, 2).
The acute, as well as chronic, toxic effects of ethanol may include irreversible organ damage. Disorders relating to memory loss, veisalgia, CNS and hepatoxicity have been well established. Also, studies have been made and theories have been postulated that cite ethanol as a cause for physiological disorders.
The invention focusses on certain pathways to reduce overall toxic effect of alcohol including effects on the brain, the liver, immunology, blood plasma and alcohol-induced veisalgia. Alcohol-induced veisalgia is the adverse effects experienced in the morning after a binge drinking episode. When the symptoms of veisalgia are initiated, blood alcohol level is usually zero or close to zero. Veisalgia is characterized by a variety of symptoms including dry mouth, nausea, sleepiness, headache, light-headedness, lack of concentration, etc. Veisalgia does not have a single cause; multiple physiological, metabolic, neuro-pharmacological and neuro-immunological effects, which are triggered by binge alcohol consumption that eventually leads to the Veisalgia syndrome. Acetate could be a primary contributor to the headache component of the Veisalgia, while acetaldehyde may also cause Veisalgia symptoms in humans.
Among the symptoms of veisalgia are memory decrements (Verster et al. “Alcohol Hangover Effects on Memory Functioning and Vigilance Performance after an Evening of Binge Drinking.” Neuropsychopharmacology, 28, 2003, 740-746; McKinney and Coyle, “Alcohol Hangover Effects on Measures of Affect the Morning after a Normal Night's Drinking.” Alcohol and Alcoholism Vol. 41, No. 1, pp. 54-60, 2006). Further, it has been shown that, during veisalgia, a patient's ability to perform complex tasks is compromised, which indicates a diminishment of the patient's memory function (Kim et al. “The Effects of Alcohol Hangover on Cognitive Functions in Healthy Subjects.”International Journal of Neuroscience, 113, 2003, 581-594). Moreover, acute, as well as chronic, administration of alcohol can modulate cognition and lead to several neurocognitive effects, namely, impairment in intellectual ability, all modes of learning procedure, planning capacity, visuomotor coordination, memory, etc (Sullivan and Pfefferbaum. “Neurocircuitry in Alcoholism: A Substrate of Disruption and Repair.” Psychopharmacology, 180, 2005, 583-594).
The role of inflammatory neurodegeneration in alcohol-related neuropathology of humans suggests that the enhanced expression of Monocyte Chemoattractant Protein-1 (MCP-1) and microglia activities in alcoholic brains could contribute to ethanol-induced pathogenesis. (Jun He, Fulton T. Crews. “Increased MCP-1 and Microglia in Various Regions of the Human Alcoholic Brain.” Experimental Neurology, 210, 2, 2008, 349-358).
Alcohol Veisalgia and Immunology Factors
Crews et al. have shown glycyrrhizin inhibits High-mobility group protein B1 (HMGB1) and also acts as an Toll-like receptor 4 (TLR4) antagonist as well as inhibitor of microglial activation, all blocked ethanol-induced expression of pro-inflammatory cytokines like TNF-α and IL-1b.
HMGB1 is a highly conserved eukaryotic non-histone chromosomal protein. Upon stimulation, HMGB1 undergoes translocation from the nucleus to the cytoplasm, and it is then secreted via the lysosomal pathway in most cells by exosomes in enterocytes or by the inflammasome in immune cells. HMGB1 can trigger an inflammatory response, when passively released from injured or necrotic cells due to loss of membrane integrity or when secreted by activated monocytes and macrophages as a delayed response to lipopolysaccharide. HMGB1 expression, translocation and secretion progressively increase, both in liver and serum, during alcoholic liver diseases (Xiaodong Ge, et al 2014 Journal of biological chem., 289, 33, 22672-22691).
These results support the hypothesis that ethanol alters histone deacetylase (HDACs) that regulates HMGB1 release and that danger signal HMGB1 as endogenous ligand for TLR4 mediates ethanol-induced brain neuro-immune signalling through activation of microglial TLR4. These findings provide new therapeutic targets for brain neuro-immune activation and alcoholism (Zou J Y, Crews F T. “Release of Neuronal HMBG1 by Ethanol Through Decreased HDAC Activity Activates Brain NeuroimmuneSignaling.” PLoSONE, 9, 2, 2014, e87915.
Among the hangover veisalgia symptoms, incidence of headaches is most common. Headaches may be explained not only by the vasodilatation effects of alcohol but also by increases in serotonin, histamine, and prostaglandin levels (Pattichis et al., Eur J Pharmacol, 292, 1995, 173-177) or by a profound deficit in ionized Mg++, which may be reversed by the administration of MgSO4 (Altura and Altura, 1999, Alcohol, Vol. 19, No. 2, pp. 119-130). Recent findings suggest that higher levels of cytokines could also lead to a hangover veisalgia headache. Some researchers also demonstrated that acetate could also contribute to the hangover veisalgia headache by increasing adenosine in the brain tissues (Christina R. Maxwell, et al, Acetate causes alcohol hangover headache in rats, Plos one, 5, 12, 2010, 01-09). Apart from these, acetaldehyde and congener content contribute a small but significant additional effect.
Further, physiological changes during a state of veisalgia, in particular, nausea, headache, and fatigue have been suggested to be mediated by changes in immune system function. The state of veisalgia has been defined as being initiated 13 hours after drinking 1.5 g/kg of alcohol (blood alcohol level). The values of the cytokines like Interleukin (IL), IL-10, IL-12 and IFN-α shows significant increase 13 hours after alcohol consumption. An increase in production of IL-10, as a response to pro-inflammatory cytokine production, thus supports the suggestion of impaired cellular immunity during Veisalgia (Kim et al. “Effects of Alcohol Hangover on Cytokine Production in Healthy Subjects.” Alcohol, 31, 3, 2003, 167-170).
Oxidative Stress and Liver
There are three principal reaction mechanisms capable of oxidizing ethanol to acetaldehyde. These are the alcohol dehydrogenase (ADH), catalase and microsomal ethanol oxidizing systems (MEOS). Acute studies involving a single dose of ethanol primarily metabolized through alcohol dehydrogenase system without significant involvement of catalase. However, chronic exposure of ethanol may involve catalase pathway, as a minor pathway, as demonstrated by the large amounts of catalase found in various tissues and the presence of various peroxide-generating systems. MEOS is a mixed function oxidase system in mammalian liver microsomes, which plays a major role in hepatic metabolism of many drugs including ethanol to acetaldehyde by nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) and oxygen-dependent oxidation by cytochrome P-450s (Hawkins R D, Kalant H. “The Metabolism of Ethanol and its Metabolic Effects.” Pharmacological Review 24, 1 1972, 67-157). Further, cytochrome P450 (CYP) 2E1-dependent microsomal monoxygenase system, the mitochondrial respiratory chain and the cytosolic enzymes xanthine oxidase and the aldehyde oxidases have been implicated as sources of O2 and H2O2 in parenchymal cells during ethanol intoxication (Albano E. “Alcohol, Oxidative Stress, and Free Radical Damage. Proceedings of the Nutrition Society, 65, 03, 2006, 278-290). CYP2E1-dependent monoxygenase activity increases by 10-20fold in chronic alcoholism (Liangpunsakul et al. “Activity of CYP2E1 and CYP3A Enzymes in Adults with Moderate Alcohol Consumption: A Comparison With Nonalcoholics.” Hepatology, 41, 5, 1144-50). In liver, the CYP2E1 content is positively correlated with NADPH oxidase activity and lipid peroxidation (Ronis et al., “The Role of Ethanol Metabolism in Development of Alcoholic Steatohepatitis in the Rat”, Alcohol. 44, 2, 2010, 157-169.). Thus, one of the major sources of reactive oxygen species (“ROS”) of ethanol-induced oxidative stress is the alcohol-inducible cytochrome P450 (CYP) 2E. The other main contributing factors that produce ROS are the mitochondrial electron transport chain reactions, activated phagocytes and impairment of endogenous antioxidant defences.
The primary pathway of alcohol metabolism, when alcohol is consumed below moderate amounts, is catalysis in the cytoplasm of hepatocytes by alcohol dehydrogenase (ADH) to form acetaldehyde. The accumulation of NADH in the liver seems to be critical in liver damage in chronic alcohol use. Acetaldehyde produced through microsomal ethanol oxidation system (MEOS) accounts for less than 10% of the liver capacity to oxidize ethanol. At higher alcohol levels (>100 mg/dl), MEOS involves CYP450 (2E1, 1A2 & ‘3A4), which plays a pivotal role in alcohol metabolism using NADPH as a cofactor and O2. (Koop, D. R., “Alcohol Metabolism's Damaging Effects on the Cell.”, Alcohol Research & Health, 29, 4, 2006, 274-280). Acetaldehyde is oxidized to acetate in the liver via mitochondrial nicotinamide adenine dinucleotide (NAD+) dependent aldehyde dehydrogenase (ALDH). ADH activity is 3 times more than ALDH, and so accumulation of Acetaldehyde takes place. Acetate is further metabolized to acetyl CoA and can enter the TCA cycle or synthesis of fatty acids. Each of these pathways results in the formation of free radicals (such as ROS) with concomitant changes in the cell's redox state (i.e., nicotinamide adenine dinucleotide (“NAD+”) reduced by two electrons). (Wheeler M D. et al. “The Role of Kupffer Cell Oxidant Production in Early Ethanol-Induced Liver Disease.” Free Radical Biology & Medicine, 31, 12, 2001, 1544-1549). The redox state in relation to alcohol metabolism causes inhibition of NAD+-mediated enzyme reactions typical to the normal metabolism of the hepatocyte, leading to positive NADH/NAD+ ratio, which causes alcohol-induced fatty liver production, which leads to oxidative stress through a variety of pathways mentioned above. (Zakhari, S. “Overview: How is Alcohol Metabolized by the Body?” Alcohol Research & Health, 29, 4, 2006, 245-255). Alcohol induced derangements of hepatic lipid metabolism results in steatosis. Initially the primary reason was thought to be redox shifts generated by the oxidation of ethanol by alcohol and aldehyde dehydrogenases that eventually inhibit beta oxidation caused by accumulation of NADH and product inhibition of the mitochondrial fatty acid-oxidizing dehydrogenases. Later on many new mechanisms for alcoholic steatosis have been suggested which are interrelated and provide a more comprehensive picture of how alcohol abuse deranges hepatic lipid metabolism and results in steatosis. These include oxidative stress, mobilization of peripheral triglyceride from the adipose tissue to the liver, alterations of transcriptional controls of lipid metabolism and increased hepatic lipid synthesis in responses to alcohol (Sozio M and Crabb D W. “Alcohol and Lipid Metabolism.”, Am J Physiol Endocrinol Metab, 295, 1, 2008, E10-E16).
Liver and Immunological Factors
The forms of alcoholic liver diseases (ALD) are simple fatty liver (steatosis), fatty liver accompanied by inflammation (steatohepatitis) leading to scar tissue formation (fibrosis), and the destruction of the normal liver structure (liver cirrhosis), which may or may not improve with abstinence and subsequently might lead in liver cancer (hepatocellular carcinoma). Liver cirrhosis is the 12th leading cause of death in United States. (Szabo, Gyongyi. “Alcohol and Health: Focus On: Alcohol and the Liver.”, National Institute of Alcohol Abuse and Alcoholism, 40, 2010, 87-96).
Another plausible pathway of alcohol induced hepatotoxicity includes excess production of pro-inflammatory cytokines by gut-endotoxin stimulated Kupffer cells. ROS is mainly generated in association with the mitochondrial electron transport system; it is also produced by CYP2E1 and by activated Kupffer cells in the liver. Both acute and chronic alcohol consumption can increase ROS.
The mechanisms for the progression of alcohol induced liver injury are complex and dynamically regulated over time and hepatocellular location. Multiple mechanisms of cellular injury are involved during development of alcohol induced liver diseases. Programmed cell death or apoptosis is one of the major modes of hepatic cell death during alcohol liver diseases (Elmore, S. “Apoptosis: A Review of Programmed Cell Death.”, Toxicologic Pathology, 35, 4, 2007, 495-516). Apart from apoptosis, there are two types of cell death, which have been described: necrosis and necroptosis (Zhang, et al. “RIP3, an Energy Metabolism That Switches TNF-Induced Cell Death from Apoptosis to Necrosis.” Science, 325, 5938, 2009, 332-336) which are caused due to cascade of reaction, based on the activity of immune mediators. The liver acts as a vital immune organ comprising a large pool of natural killer cells and Kupffer cells, factors to initiate and propagate immune reactions (Gao et al. “Liver: An Organi with Predominant Innate Immunity.” Hepatology, 47, 2, 2008, 729-36). Kupffer cell activation plays a pivotal role in alcoholic liver disease. A series of soluble innate immune factors and mediators including pro-inflammatory cytokines also play a crucial role in the development of alcohol induced liver diseases. Several pro-inflammatory cytokines are upregulated in the liver in response to alcohol exposure. Among them TNF-α, secreted from Kupffer cells, is a critical mediator (Wang, G., Manning, M L, and Amack J D. “Regional Shape Changes Control Form and Function of Kupffer's Vesicle in the Zebrafish Embryo.” Dev Biol, 370, 1, 2012, 52-62). Production of TNF-α has also been stimulated by exposure of Lipopolysaccharide (LPS). Apart from TNF-α, IL-1β is another potent component that triggers liver damage.
Interleukin-22 (IL-22), cytokine that is produced by Th17 and NK cells, plays an important role in ameliorating alcoholic liver injury, controlling bacterial infection, homeostasis, and tissue repair. (Sung Hwan K et al., Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: Role of STAT3, Hepatology, 52, 4, 2010, 1291-1300).
IL-17 has been reported to play role in Human alcoholic liver disease, which is characterized by the activation of the IL-17 pathway by liver infiltration with IL-17-secreting cell infiltrates as a key feature that might contribute to liver neutrophil recruitment. (Arnaud Lemmers et al., The Interleukin-17 Pathway Is Involved in Human Alcoholic Liver Disease, 49, 2, 2008, 646-657.
Description of the Related Art
Liquor (alcoholic beverage) is a beverage containing ethyl alcohol. The functional alcoholic beverage of the present invention includes liquor so that the final alcohol concentration is 1.0-50.0%. The following prior art exists in the field of this invention:
WO1989004165A1 or EP0336960A4 divulges alcoholic beverages with combination of any one or more sugars from the group consisting of D-galactose, D-lactose, D-xylose, L-fructose, D-mannitol, sorbitol, D-glucose etc.
JP06014746 discloses alcoholic beverages comprising a glycoside of quercetin, divalent metallic ion and licorice extract (Glycyrrhizin). This beverage enhances alcohol metabolism and has hepatopathy-suppressive activity, due to ethanol and acetaldehyde. Thus, it reduces veisalgia.
WO2002017939 discloses Glycyrrhizaglabra, (glycyrrhizin), which facilitates the absorption and enhance uptake of herbal extracts, variety of drug molecules from anti-infective and anti-cancer category, nutraceutical compounds.
CN 1736270 discloses a liver-protecting drink constituting Chitosan oligosaccharide, glycyrrhizin, aqueous extract of kudzuvine flower and aqueous extract of hovenine.
JP2008266203 and EP0502554 discloses an increase in amount of an enzyme activity of the Reactive oxygen species (ROS) scavenging enzyme group such as superoxide dismutase, catalase or peroxidase with one or more kinds of substances selected from the group consisting of erythritol, mannitol, sorbitol and xylitol.
U.S. Pat. No. 4,987,123 A unveil an amino acid or oligopeptide containing either a L-alanine residue or a L-glutamine residue, or both in the therapy or prevention of alcoholic hepatic disorders.
Japanese Patent JP2000072669 divulges specific composition of amino acids and trehalose combination, which compensates the decrease in blood amino acids due to hard physical exercise and fatigue.
Japanese Patent JP63036773A discloses an alcoholic drink having excellent taste, flavour, nutrient and stability over a long period, which mainly contains amino acid such as glycine, alanine, tyrosine, etc., and sugar such as sorbitol, sucrose, fructose, etc.
CN 103404934 A unveil beverage consisting glutamine, alanine, methionine, ganoderan, vitamin C, maltitol, citric acid, and beta-cyclodextrin, which protects from Veisalgia, stomach and liver, promoting urination and improving immunity.
U.S. Pat. No. 6,713,091 B1 reveals composition amino acid & liquorice lowering the concentration of alcohol in blood.
CN 103445175A discloses composition comprising of synanthrin, xylitol, aminopropionic acid, alanine, and glutamine. This alleviates Veisalgia and protects liver.
CN 101332289A discloses liquorice extract, field turnip extract, fresh ginger extract, amino acid, vitamin, taurine, folic acid, calcium, magnesium, zinc and kalium. This formulation protects the liver from alcohol toxicity.
WO/2014/177989 is Applicant's own patent application and discloses reduced toxicity of functional alcoholic beverage comprising 18β-Glycyrrhizin or 18α-Glycyrrhizin and a sugar alcohol or sugars as synergistic hepato-protectants.
CN 103622981A discloses an invention containing glycyrrhizin, cysteine hydrochloride (amino), glycine (amino) and a pharmaceutic adjuvant like mannitol (sugar alcohol). The ratio of glycyrrhizin to cysteine hydrochloride to glycine is 1:1:1 for liver disease dermatology field, the field of cancer chemotherapy protection and other diseases.
CN 1706394A discloses ammonium glycyrrhizinate, cysteine hydrochloride, glycine, sodium bisulfite, and mannitol in certain proportion for skin disease and viral disease.
CN 1985987B relates synergistic combination 150 parts diammoniumlicorice and glutathione 300 copies in treating liver diseases, high stability, and wide application.
CN 1709272A invention reveals diammoniumglycyrrhizinate, cystine, glycine, methionine and vitamin B1 for curing the liver diseases & improving function of liver and cholestasis in the liver. It could also be used for auxiliary therapy of alcoholism and barbitones and sulfonamides drug poisoning. The combination ratio for diammoniumlicorice, cysteine and glycine is 3 to 5:2 to 4.30:50.
CN101633683 discloses 18-alpha or 18-beta glycyrrhizin, L-glutamic acid & mannitol for anti-hepatitis drug.
CN101669962A discloses 18-alpha and 18-beta glycyrrhizin (ratio 1 to 20:1), amino acid & xylitol based on literature claim for anti-inflammation, anti-anaphylaxis, oxidation resistance, anti-atherosclerosis, immune regulation and detoxification.
CN 1586489A unveils salts of glycyrrhizinate, amino acid(s), antioxidant stabilizer(s) to improve product stability.
CN102302502 invention reveals combination of various amino acid with glycyrrhizin. U.S. Pat. No. 4,987,123 comprising L-alanine and L-glutamine available in molar ratio of 1:0.1 to 1:10 or oligopeptide for hepatic disorders.
US 20100234308 discloses oligopeptide Alanylglutamine, a dipeptide containing two amino acids, alanine and glutamine. Each may be L- or D-forms, and the L-forms are preferred for wake up remedy.
U.S. Pat. No. 4,596,825 molar ratio of ornithine to alanine in said mixture is about 1:0.001 to 10, amount effective to prevent or alleviate said alcoholic liver disturbance. US2010/0086666 A1 reveals alcohol infused with protein like casein hydrolysate.
However, none of the prior art references, discloses, or teaches combining a composition of saponin glycosides such as liquorice or glycyrrhizin or glycyrrhizin derivative or its pharmaceutically acceptable salts, a sugar alcohol or sugar and, an Amino-Acid Derivative amino-acid or peptide residue, with distilled alcohol and deionized water.
Also, none of the prior art discloses or teaches a combination for modulating the immunology response, and thereby alleviating CNS stress.
In addition, none of the prior art discloses or teaches a synergistic composition for alleviating of hepatic stress. Further, none of the prior art discloses or teaches a synergistic composition modulating immunology parameter, alleviating oxidative stress and veisalgia.